Over 4 million U.S. men and women suffer from Alzheimer's disease; 1 million from Parkinson's disease; 350,000 from multiple sclerosis (MS); and 20,000 from amythrophic lateral sclerosis (ALS). Worldwide, these four diseases account for more than 20 million patients. Although great progress has been made in recent years toward understanding of these diseases, few effective treatments and no cures are currently available mainly due to the impermeability of the blood-brain barrier (BBB). Safe and localized opening of the blood-brain barrier (BBB) has been proven to present a significant challenge in brain drug delivery. Of the methods used for BBB disruption shown to be effective, Focused Ultrasound (FUS), in conjunction with microbubbles, is the only technique that can induce localized BBB opening noninvasively and regionally. The underlying hypothesis of this study is that, through control over the ultrasound and microbubble parameters, the extent and reversibility of the BBB opening induced by FUS can be successfully predicted and manipulated for efficient trans-BBB delivery. The primary objective of this study is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS. In addition, the mechanism of the BBB opening in vivo will be monitored by the use of an MR contrast agent attached to the microbubble shell, which will allow observation of the location and accumulation of the shell material following treatment. The team assembled encompasses all important specialty areas required, such as ultrasound and microbubble engineering as well as MR and fluorescence brain imaging. The specific aims of the study are to: 1) engineer and determine the microbubble characteristics for a reversible and localized BBB opening; 2) identify the mechanism of BBB opening at distinct microbubble and ultrasound parameters in vivo; 3) perform quantitative analysis of the BBB opening using MR and fluorescence imaging; and 4) image the mechanism of BBB opening and trans-BBB delivery in vivo. By achieving the goals of the proposed study, the mechanism of the FUS procedure will be more thoroughly understood and the FUS-induced BBB opening will be optimized for selectively and precisely delivering pharmacological agents to currently untreatable brain regions. Public Health Relevance Statement (provided by applicant): Due to the impermeability of the blood-brain barrier (BBB), neurological disorders and all age-related neurodegenerative diseases remain untreatable despite the thousands of pharmacological agents available. The objective of this study is to elucidate the interactions between ultrasound, microbubbles and the local microenvironment during BBB opening with FUS.